A Practical Classification of Childhood Hypopigmentation Disorders

Home , Cross syndrome, Elejalde syndrome, Griscelli syndrome, Hypopigmentation, Nevus anemicus, Nevus depigmentosus

Acta Derm Venereol 2010; 90: 6–11

MINI-REVIEW A Practical Classification of Childhood Hypopigmentation Disorders

Hong Liang Tey National Skin Centre, 1, Mandalay Road, Singapore, Singapore

Hypopigmentation disorders in children can be due to a Onset in early childhood wide variety of congenital and acquired diseases. A clinical approach to hypopigmentation disorders based on In this article, disorders that present in early childhood the typical age of onset and the extent of lesions is propo- describe those disorders that occur up to the first 2 sed. The disorders are categorized into onset in early and years of life. Most of these disorders present at birth later childhood, and in each category they are subdivi- or during infancy and have a genetic basis. Clinically, ded into localized and generalized pigmentary disorders. these disorders can be divided into those characterized Clinical findings, comprising the sites of involvement, by generalized hypopigmentation and those causing degree of pigment loss, and associated morphological fin- localized disease. dings, are used to distinguish the disorders further. This classification provides a systematic approach to a clinical Generalized hypopigmentary disorders condition in which the causes are heterogeneous and his- Disorders with generalized diffuse pigmentary dilution tological examination of the skin is rarely diagnostic. Key are usually due to mutations of genes responsible for words: approach; childhood; pediatric; hypopigmentation; the production of melanin or the processing of melano hypopigmented. somes, and hypopigmentation of the skin and hair is (Accepted October 26, 2009.) present. During embryogenesis, progenitor melanob- lasts migrate between mesodermal and ectodermal lay- Acta Derm Venereol 2010; 90: 6–11. ers to reach their final destinations in the epidermis and hair follicular bulbs, as well as the inner ear cochlea, Hong Liang Tey, National Skin Centre, 1, Mandalay Road, choroids, ciliary body, and iris (1). Therefore, the eyes, Singapore 308205, Singapore. E-mail: teyhongliang111@ in addition to the skin and hair, can exhibit pigmentary yahoo.com dilution. In a group of generalized hypopigmentary disorders, hypopigmentation involves the eyes in addition to the skin and hair, and this group has been typified as The colour of the skin is mainly due to melanin and blood oculocutaneous albinism (Fig. 1). but can be altered in non-physiological conditions such as Oculocutaneous albinism (OCA) is the most common carotenemia, drug intake, jaundice and chronic renal fai- type of pigmentary dilutional disorder, of which type 2 lure. Hypopigmentation refers to any form of decreased comprises the majority of the cases. In OCA type 1A, in pigmentation, whereas hypomelanosis refers specifically which there is complete absence of tyrosinase activity, to a decrease in melanin content. Depigmentation, in there is permanent and complete absence of pigment from contrast to hypopigmentation, describes the almost total birth. In OCA types 1B, 2, 3, and 4, however, pigment loss of pigmentation, resulting in a whitish appearance production may increase over time. In these latter types that comes from the underlying dermis. of OCA and including Hermansky–Pudlak and Chediak– Hypopigmentation disorders can generally be cate- Higashi syndromes, the pigmentary dilution may be gorized based on their aetiologies, age of onset, and subtle, and comparison with family members will be extent of involvement. In early childhood, many of helpful. This is especially so in fair-skinned races. these disorders have a genetic origin and present with Common to all types of OCA, there is reduced visual generalized pigmentary dilution. In later childhood, acuity and ocular nystagmus (2) and these distinguish many of these diseases are acquired and cause localized OCA from other forms of congenital hypopigmentation. hypopigmentation. Other clinical features can aid in The ocular abnormalities are due to misrouting of the the further differentiation of these disorders, such as optic nerve and this may result from deficiency of tyro- the sites of involvement, degree of pigment loss, and sinase. Tyrosine hydroxylase, in particular, is important associated morphological signs. In the clinical approach in the proper routing of retinal projections at the optic to be presented here, the disorders are categorized pri- chiasm during development (3). Infants who are unable marily according to the typical age of onset into early to fixate or have nystagmus should be sent for a thorough and later childhood. ocular examination as early intervention is crucial for

Onset in early childhood melanolysosomal disease, is characterized Generalised hypopigmentation by silvery hair, mild hypopigmentation,

Eyes, skin and severe central nervous system dysfun- Skin and hair and hair ction (6). Its molecular basis is currently not known. Oculocutaneous Inborn errors Nutritional Genodermatoses albinism of metabolism deficiencies Menkes syndrome is an X-linked recessive multi-systemic disorder due to Defects in Defects in Unknown Phenylketonuria Neurologic melanin packaging of Copper inappropriate intracellular copper storage. mechanism defects production melanosomes It is typified by hair shaft abnormalities, Homocysteinuria Griscelli and Hermansky- Cross Elejalde OCA 1-4 Pudlak syndrome of which pili torti is the most common. syndromes Selenium syndrome Histidinaemia Pigmentary abnormalities consist of Menkes Prader-Willi & Chediak-Higashi syndrome lightly pigmented hair and generalized Angelman syndrome syndromes or localized hypopigmentation. Progres- Skeletal defects sive central nervous system deterioration occurs and results in death by 3 years of EEC syndrome age (7). Fig. 1. Generalized hypopigmentation with early onset. Pigmentary dilution and skeletal defects occur in Ectrodactyly-Ectodermal dysplasia-Cleft lip/palate (EEC) syn- visual development. In addition, hypopigmented babies drome. The “lobster-claw” deformities of the hands should undergo a systemic evaluation to exclude other and feet and cleft lip and palate enable the syndrome rarer disorders. For example, the presence of mental retar- to be recognized easily. The cutaneous features consist dation suggests Angelman and Prader–Willi syndromes, of diffuse hypopigmentation and dryness of the skin an obese baby may have Prader–Willi syndrome, bleeding and hair (8). diatheses may be a sign of Hermansky–Pudlak syndrome, Loss of hair and skin pigmentation due to selenium immune deficiency points to Chediak–Higashi syndrome, deficiency has been described in children receiving and structural ocular and neurological abnormalities sug- long-term total parenteral nutrition, and repigmentation gest Cross syndrome. occurred after selenium supplementation (9). Hypopig- Impairment of melanin synthesis occurs in certain mentation of the skin and hair has also been described diseases of inborn errors of metabolism, such as phenyl- in severely malnourished infants, and this was attributed ketonuria, homocystinuria and histidinaemia, which are to copper deficiency because tyrosinase is a copper- due to the absence or defect in phenylalanine hydroxy- dependent enzyme. However, as multiple nutritional lase, cystathionine synthetase, and histidase, respecti- deficiencies tend to co-exist, the pathogenesis was dif- vely. These three disorders are transmitted in an auto- ficult to confirm (10). somal recessive manner and are associated with mental In all of the disorders outlined in Fig. 1, the epidermis retardation and other systemic dysfunction. generally contains normal numbers of melanocytes and Some genetic disorders result in pigmentary dilution histology of the skin is not helpful in differentiating of the skin and hair, but spare the eyes. The patients these conditions. The pathophysiological defect of should be screened for systemic abnormalities and if hypopigmentation lies either in melanin biosynthesis neurological defects are present, the differential di- or melanosome formation and trafficking. Disorder of agnoses will include Griscelli, Elejalde and Menkes melanin biosynthesis can be due to tyrosinase defects syndromes. Griscelli and Elejalde syndromes are rare, (occurring in OCA types 1 and 3 and copper deficiency) autosomal recessive disorders with abnormalities in the or melanosomal dysfunction (occurring in OCA types transport of lysosome-related organelles, which include 2 to 4). Abnormalities in the formation, transport, and melanosomes, platelet-dense bodies and lymphocyte transfer of melanosomes occur in Hermansky–Pudlak, lytic granules (4). Besides cutaneous pigmentatory dilu- Chediak–Higashi, and Griscelli syndromes. tion, the consequence of disrupted melanosome transfer is silver discoloration of the hair, which can be seen to contain multiple clumps of melanin under light micro Localized hypopigmentary disorders scopy. In fact, Griscelli, Elejalde and Chediak–Higashi Localized hypopigmentation presenting in early child- syndromes have been termed “silvery hair syndromes” hood can be due to genetic or acquired causes. These (5). Apart from pigmentary dilution and neurological disorders can clinically be categorized based on whether abnormalities, Griscelli syndrome is also characterized the lesions are depigmented or hypopigmented (Fig. 2). by immunological impairment. There are three types of Piebaldism and vitiligo are both characterized by the disease known currently, and Elejalde syndrome has an absence of epidermal melanocytes and the clinical the same clinical features as Griscelli syndrome type presentation of depigmentation. Unlike vitiligo, lesions 1. Elejalde syndrome, also known as neuroectodermal in piebaldism are present at birth and almost always re-

Acta Derm Venereol 90 8 H. L. Tey

Onset in early childhood with generalized, instead of patchy hypopigmentation and Localised hypopigmentation complete, instead of variable hearing loss (13). In an infant who presents with a single hypopigmented macule or patch, the main differential diagnoses are nevus Depigmented Hypopigmented depigmentosus, an ash leaf macule of tuberous sclerosis, and nevus anemicus. Nevus anemicus is a localized Piebaldism vascular anomaly in which the vessels are hypersensitive Vitiligo Waardenburg syndrome Congenital Acquired to catecholamines and it can be distinguished from the Tietz syndrome hypomelanotic disorders in a few ways. Using diascopy, nevus anemicus can be made to blend into the surroun- Naevus Post-inflammatory ding blanched skin. Nevus anemicus is not accentuated anaemicus hypopigmentation by Wood’s lamp, in contrast to lesions which contain less Ash-leaf macule melanin. The reflex vasodilatory response is also absent

in tuberous upon application of pressure and heat; scratching a line sclerosis across nevus anemicus will not induce erythema in the Naevus depigmentosus lesion and the contrast can be seen in the surrounding & hypomelanosis of Ito (pigmentary mosaicism) normal skin. The most common causes of a single hypomelanotic Fig. 2. Localized hypopigmentation with early onset. patch are nevus depigmentosus and an ash-leaf macule of tuberous sclerosis. The diagnosis of tuberous main stable throughout life. There are usually normally sclerosis becomes more likely if there are multiple pigmented to hyperpigmented skin as islands within the hypomelanotic macules (only about 10% of patients depigmented patches and at the lesional borders in pie- with tuberous sclerosis present with a single hypome- baldism. The lesions are classically distributed over the lanotic lesion) (14) or if the lesion is lance ovate-shape mid-forehead, anterior trunk and mid-extremities, and like ash leaves (rounded at one end and pointed at the they are hardly ever found near the midline on the back – other). Ash-leaf macules are usually the first manifesta- this is due to the embryonic pattern of dorso-ventral mig- tion of tuberous sclerosis and the other cutaneous featu- ration of melanocytes. The c-KIT and SLUG genes have res, such as facial angiofibromas, only start appearing been found to be mutated in piebaldism. Dysfunction of after the age of 5 years (15). The diagnosis of tuberous the protein product, a tyrosine kinase transmembrane sclerosis may therefore only be apparent when the child receptor on melanocytes, leads to aborted migration and is older. Histologically, the primary finding in both survival of melanocytes in the skin (11). nevus depigmentosus and ash-leaf spot is a decrease in In patients presenting with signs of piebaldism, it is epidermal melanin content. Ultrastructural differences important to check for features of Waardenburg syn- have been described, consisting of a decrease in the drome (WS), which include heterochromia irides and a transfer of melanosomes in nevus depigmentosus and a broad nasal root. In WS type 1, dystopia canthorum is decreased number of melanosomes in tuberous sclerosis present in addition to these features (12). In WS type 2, (16). The differentiation between nevus depigmentosus unlike the other types of WS, sensorineural deafness is and tuberous sclerosis remains clinical. common. WS type 3 consists of limb defects in addition Hypomelanosis of Ito is a descriptive term for streaks to features of type 1 disease and WS type 4 consists of of hypopigmentation that presents in infancy. It is not a Hirschsprung disease in addition to features of type 1 specific diagnosis and it may occur as a consequence of disease. It is therefore important to screen for hearing several different chromosomal abnormalities that perturb and musculoskeletal defects and chronic constipation in various genes relevant to skin pigmentation. Although an infant with dysmorphic features of WS. In WS, there the characteristic configurations are whorled and linear, is a failure of melanocytes to migrate and survive in the the lesions can be patchy as well. On the other hand, epidermis, hair follicles, irides and inner ear. Certain there is a variant of nevus depigmentosus that consists genes are involved in neural crest development and of segmental or linear hypopigmentation and this overlap mutations of these genes in WS type 4 lead to defects with hypomelanosis of Ito clinically. Some clinicians of both melanocyte development in the various organs have use the term “naevoid linear hypopigmentation” to and neuronal development in the distal colon (leading to encompass both conditions (17). Upon the diagnosis of Hirschsprung disease or congenital aganglionosis). In WS hypomelanosis of Ito, it is essential to exclude associated type 2, the microphthalmia-associated transcription factor systemic abnormalities, which occurs in about one-third (MITF) gene is mutated and mutation of the same gene of children (18), affecting the central nervous and mus- can also lead to Tietz syndrome. Tietz syndrome is clini- culoskeletal systems and the heart particularly. cally distinguishable from WS type 2 in that the former The lesions in hypomelanosis of Ito tend to fol- is characterized by a more severe phenotype, presenting low the lines of Blaschko, which are believed to be

Acta Derm Venereol 90 Childhood hypopigmentation 9 pathways of migration and proliferation of epidermal Onset in later childhood cells during embryogenesis. The bands of abnormally Generalised hypopigmentation pigmented skin represent clones of cells carrying a mutation in a gene expressed in the skin. Apart from somatic mutations, mosaicism following the lines Depigmented Hypopigmented of Blaschko is also seen in chromosomal mosaicism and functional mosaicism (random X-chromosome Vitiligo inactivation through lyonization). Clinically, these universalis Inborn errors Malnutrition disorders present with linear pigmentary changes as of metabolism one of their features. The linear or segmental variant Copper of nevus depigmentosus, hypomelanosis of Ito, and Homocysteinuria linear and whorled hyperpigmentation are probably a deficiency phenotypic spectrum of such genetic mosaicism and Selenium Histidinaemia have recently been classified under the term “pigmen- deficiency tary mosaicism”. The important genodermatoses presenting with Fig. 3. Generalized hypopigmentation with late onset. pigmentary dilution and hypopigmented lesions in the infancy period are listed in Table I. The disorders have onset pigmentary dilutional disorder. The causes and been classified according to their pathogenetic defects approach are presented in Fig. 3. in melanogenesis. Homocysteinuria and histidinaemia (also known as his- tidinuria) usually present during early childhood. Central nervous system disorders are features of both diseases Onset in later childhood and musculoskeletal and cardiovascular abnormalities Disorders which typically presents after the first one to are also present in homocysteinuria. two years of life are included here. Most of these are acquired in origin. Similar to those presenting in early Localized hypopigmentary disorders childhood, these diseases can be clinically divided into those characterized by generalized hypopigmentation Hypopigmentary disorders presenting in later child- and those causing localized disease. hood are usually localized. The common causes are presented in Fig. 4. Generalized hypopigmentary disorders Vitiligo is characterized clinically by depigmented macules and patches that correspond histologically to Generalized hypopigmentation presenting in an older a decrease or absence of melanocytes in the epidermis child is uncommon. The causes include vitiligo univer- and, less often, the hair follicles. Its most common age salis (presenting with depigmentation), inborn errors of onset is 10–30 years of age, with a mean age of 20 of metabolism (homocysteinuria and histidinaemia), years. In general, vitiligo can be categorized based on malnutrition (in particular copper and selenium de- the distribution into localized, generalized, and univer- ficiency), and a delay in the diagnosis of an infancy- sal forms. Localized forms can be segmental, focal, or

Table I. Underlying defects in genodermatoses with pigmentary dilution or hypopigmented lesions (from ref. 19)

Defect Disease Gene Locus Proliferation and migration of melanocytes Piebaldism c-kit 4q12 Waardenburg syndrome (WS) WS1 and WS3: PAX3 2q35 WS2A: MITF 3p14.1–p12.3 WS4: SOX10, EDN3, EDNRB 22q13, 20q13.2–13.3, 13q22 Tietz syndrome MITF 3p14.1–p12.3 Production of melanin Oculocutaneous albinism (OLA) OCA1: TYR 11q14–q21 OCA2: OCA2 15q11.2–q12 OCA3: TYRP1 9p23 OCA4: MATP 5p13.3 Prader-Willi and Angelman syndrome OCA2 (gene causing hypopigmentation) 15q21 Menkes syndrome ATP7A Xq13.2–13.3 Packaging of melanosomes Chediak–Higashi syndrome LYST 1q42.1–q42.2 Hermansky–Pudlak syndrome Type 1: HPS1 10q23.1 Tuberous sclerosis TSC1, TSC2 9q33–q34, 16p13.3 Transfer of melanosomes Griscelli syndrome Type 1: MYO5A 15q21.1 Type 2: RAB27A 15q21.1 Type 3: MLPH (or MYO5A F-exon del) 2q37 Incontinentia pigmenti NEMO Xq28

Acta Derm Venereol 90 10 H. L. Tey

Onset in later childhood sociated with epidermal atrophy and dermal induration. Localised hypopigmentation Up to 15% of cases occur in children, and the lesions in the majority of these cases occur at the vulva with Depigmented Hypopigmented absence of extragenital manifestations. Possible pathogenetic mechanisms in the development of this leuko- Post-inflammatory Lichen sclerosus Vitiligo Mycosis fungoides hypopigmentation and Morphea derma include decreased melanin production, blocked transfer of melanosomes to keratinocytes, and loss of

Eczema and melanocytes (20). Lichen sclerosus and morphea have Pityriasis alba been considered to be closely related by many authors, Pityriasis but this remains controversial. lichenoides chronica Hypopigmentation is not uncommonly seen in lesions

Lichen striatus of localized scleroderma (morphea) and systemic sclerosis. The lesions may mimic vitiligo and the clues to Post infection the diagnosis of scleroderma include the presence of perifollicular hyperpigmentation (forming a “salt and Trauma pepper” dyschromatosis) and induration of the dermis. The epidermal melanocytes in the interfollicular regions Fig. 4. Localized hypopigmentation with late onset. disappear, but those in the near vicinity of hair follicles are retained. This is in contrast to vitiligo in which me- mucosal and generalized forms can be acrofacial or the lanocytes in both regions are affected. In re-pigmenting vulgaris type. Established generalized and segmental vitiligo, re-pigmentation typically starts in the perifol- forms are usually easily recognized as depigmented licular region, and differentiating it from scleroderma patches in their typical distribution and configuration, can sometimes be difficult. respectively. However, focal and mucosal types of vi- The hypopigmented variant of mycosis fungoides (MF) tiligo can be difficult to recognize, especially for early is a rare condition in childhood or adolescence (21), but lesions that are not yet depigmented. The following, if this variant seems to be more frequent in children com- present, can help support the diagnosis of vitiligo in pared to other types of MF (22). This condition should be ambiguous cases: leucotrichia, Koebner phenomenon, considered if there are scattered irregular hypopigmented halo naevi, and associated autoimmune diseases, such patches on non-sun exposed areas of the body and one as thyroid abnormalities and alopecia areata. should search for typical patch, plaque and tumour lesions A common cause of post-inflammatory hypopig- of MF, which may be present concurrently. Histologically, mentation in older children is pityriasis alba and this epidermotropism of atypical lymphocytes may be seen is typically limited to the face. Post-inflammatory hy- together with a decrease or absence of epidermal melanin popigmentation is also commonly seen in association and pigmentary incontinence. with atopic dermatitis as well as with other forms of eczema. The decrease in pigmentation can be the result of a disruption in the transfer of melanin to keratino- Investigations cytes secondary to the inflammatory process or the application of potent topical corticosteroids. In addition, Investigations are dependent on the diagnoses suspec- post-inflammatory hypopigmentation in children can ted. In congenital hypopigmentary disorders, karyo- also be due to pityriasis lichenoides chronica and lichen typing and molecular genetic analysis of the skin and striatus. When an older child presents with widespread blood may be considered, especially when the child 3–6 mm macular hypopigmentation, pityriasis lichenoi- has associated developmental delay or structural abnor- des chronica should be considered. In lichen striatus, malities. In conditions which exhibit mosaicism, skin the hypopigmentation is typically linear following the biopsy plays a more important role in the diagnosis and lines of Blaschko and multiple small, flat-topped papu- blood tests are of limited use. However, the advanced les may be seen. Post-infectious hypopigmentation can molecular techniques required for diagnosis of these result from superficial cutaneous infections as well as congenital disorders are not widely available. Biopsy childhood viral exanthems and varicella. Post-traumatic of hypopigmented lesions for histology in general is hypopigmentation is also not uncommon in children due rarely diagnostic, but this is important in acquired to the frequent superficial injuries they sustain. disorders where inflammatory disorders or mycosis If the hypopigmented lesions are associated with an fungoides is suspected. atrophic epidermal surface, lichen sclerosus, morphea and the hypopigmented variant of mycosis fungoides are Management to be considered. Lichen sclerosus is a pruritic chronic inflammatory dermatosis that results in hypopigmented In general, treatment for many hypopigmented disor- to depigmented porcelain white plaques, which are as- ders is limited, especially those which are congenital

Acta Derm Venereol 90 Childhood hypopigmentation 11 in origin. Hypopigmented diseases with an associated mentation. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest inflammatory component may be treated with topical BA, Paller AS, Leffell DJ, editors. Fitzpatrick’s dermatology in general medicine, 7th edn. New York: McGraw-Hill; corticosteroids and calcineurin inhibitors when lesions 2008, p. 609. are limited and with phototherapy when lesions are 3. Lavado A, Jeffrey G, Tovar V, de la Villa P, Montoliu L. widespread and the child is older. Autologous grafting Ectopic expression of tyrosine hydroxylase in the pigmen- of cultured and non-cultured melanocytes has been ted epithelium rescues the retinal abnormalities and visual used successfully to treat stable vitiligo and piebal- function common in albinos in the absence of melanin. J Neurochem 2006; 96: 1201–1211. dism (23). 4. Dell’Angelica EC, Mullins C, Caplan S, Bonifacino JS. The importance of sun protection, including the use of Lysosome-related organelles. FASEB J 2000: 14: 1265. a broad-spectrum sunscreen on hypopigmented lesions, 5. Van Den Bossche K, Naeyaert JM, Lambert J. The quest for should be emphasized to patients and parents. Hypopig- the mechanism of melanin transfer. Traffic 2006; 7: 769. 6. Cahali JB, Fernandez SA, Oliveira ZN, Machado MC, mented lesions are more susceptible to sun damage and Valente NS, Sotto MN. Elejalde syndrome: report of a the lesions will be more obvious with the differential case and review of the literature. Pediatr Dermatol 2004; tanning response compared with the surrounding normal 21: 479. skin. In addition, Koebner phenomenon may arise in 7. Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, lesions of vitiligo. Donsante A, et al. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med 2008; 358: 605–614. Cosmetic cover-ups for camouflage may be the only 8. Buss PW, Hughes HE, Clarke A. Twenty-four cases of the option in some hypopigmented disorders. Topical stains EEC syndrome: clinical presentation and management. J and tanning products may be used on the lesions to Med Genet 1995; 32: 716–723. decrease the colour disparity with the normal skin, and 9. Vinton NE, Dahlstrom KA, Strobel CT, Ament ME. Macro cytosis and pseudoalbinism: Manifestations of selenium most of these products contain dihydroxyacetone as the deficiency. J Pediatr 1987; 111: 711–717. active ingredient. 10. Olivares M, Uauy R. Copper as an essential nutrient. Am J The psychosocial aspect of the patient is an important Clin Nutr 1996; 63: 791S. integral part of management. This is particularly so in 11. Spritz RA. The molecular basis of human piebaldism. Pig- schoolchildren, when the hypopigmentary disorder can ment Cell Res 1992; 5: 340–343. 12. Read AP, Newton VE. Waardenburg syndrome. J Med Genet be the source of significant embarrassment and psycho- 1997; 34: 656–665. logical trauma to the developing child. Co-operation 13. Tietz W. A syndrome of deaf-mutism associated with albi- and regular communication between the physician, nism showing dominant autosomal inheritance. Am J Hum parents and school is essential, and enrolling the help of Genet 1963: 15: 259–264. 14. Ortonne JP, Mosher DB, Fitzpatrick TB. Vitiligo and counsellors and child psychiatrists should be instituted other hypomelanoses of hair and skin. New York: Plenum early when appropriate. Medical; 1983. 15. Bolognia JL. A clinical approach to leukoderma. Int J Der- matol 1999; 38: 568–572. Conclusion 16. Bolognia JL, Pawelek JM. Biology of hypopigmentation. J Am Acad Dermatol 1988; 19: 217–225. Hypopigmentation disorders in children can be due to 17. Ortonne JP. Vitiligo and other disorders of hypopigmen- a wide variety of congenital and acquired diseases. A tation. In: Bolognia JL, Jorizzo JL, Rapini RP, editors. clinical approach to hypopigmentation disorders based Dermatology, 2nd edn. Philadelphia: Mosby Elsevier; 2008, p. 928. on the typical age of onset of disease and the extent of 18. Nehal KS, PeBenito R, Orlow SJ. Analysis of 54 cases of the lesions is presented here. Further distinction of the hypopigmentation and hyperpigmentation along the lines disorders is dependent on the clinical findings, compri- of Blaschko. Arch Dermatol 1996; 132: 1167–1170. sing the sites of involvement, degree of pigment loss 19. Online Mendelian Inheritance in Man®. Available at: http:// www.ncbi.nlm.nih.gov/sites/entrez. Assecces Dec 9, 2009. and associated morphological findings. A systematic 20. Lapeere H, Boone B, Schepper SD. Hypomelanoses and approach will be useful for this clinical condition, the hypermelanoses. In: Wolff K, Goldsmith LA, Katz SI, causes of which causes are heterogeneous, and histolo- Gilchrest BA, Paller AS, Leffell DJ, editors. Fitzpatrick’s gical examination of the skin is often non-diagnostic. dermatology in general medicine, 7th edn. New York: McGraw-Hill; 2008, p. 629. The author declares no conflict of interest. 21. Neuhaus IM, Ramos-Caro FA, Hassanein AM. Hypopig- mented mycosis fungoides in childhood and adolescence. Pediatr Dermatol 2000; 17: 403–406. References 22. Ardigó M, Borroni G, Muscardin L, Kerl H, Cerroni L. Hypopigmented mycosis fungoides in Caucasian patients: 1. Holbrook KA, Underwood RA, Vogel AM, Gown AM, a clinicopathologic study of 7 cases. J Am Acad Dermatol Kimball H. The appearance, density and distribution of 2003; 49: 264–270. melanocytes in human embryonic and fetal skin revealed 23. Bondanza S, Bellini M, Roversi G. Piebald trait: implica- by the anti-melanoma monoclonal antibody, HMB-45. Anat tion of kit mutation on in vitro melanocyte survival and on Embryol (Berl) 1989; 180: 443. the clinical application of cultured epidermal autografts. J 2. Hornyak TJ. 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